In the United States, 70-90% of the approximately 1.7-3.8 million traumatic brain injuries (TBI) reported every year are considered mild and result in a wide range of acute symptoms, the cause of which are not well understood. Individuals involved in activities such as the military and athletics are at increased risk of accruing multipl TBIs. Due to natural variability involved in cases of repeated concussions in humans, animal models are instrumental in expanding our knowledge regarding the cellular consequences of mild TBI, which can include axonal injury, astrocytosis and microgliosis. Acute microglial activation may contribute to early tissue damage but has also been observed chronically after TBI and in many cases of neurodegenerative diseases where neurobehavioral consequences are evident. However, to our knowledge, no studies have focused on how microglia activation specifically affects the pathological outcomes of repeated mild TBI. We have developed a closed head injury (CHI) mouse model of concussion in which repeated concussive impacts, but not a single impact, result in acute microglial activation that is associated with greater neuron death and astrogliosis. To better understand the role of microglia in the pathology of repeated concussion, posttraumatic microgliosis will be amplified or attenuated in Aim 1. Progranulin-deficient (GRN KO) mice, which exhibit increased microgliosis compared to wildtype (WT) mice after a stab wound to the brain, will be used to elicit an enhanced microglial response after three concussions delivered at 24h inter-injury intervals. Ibuprofen, a common anti-inflammatory drug, will be given to a subset of WT mice after each injury to attenuate the normal CHI-induced microglial response. Memory, motor coordination, and anxiety-like behaviors, as well as axonal injury, neuronal degeneration, and astrocytosis will be evaluated in these three groups over the first 2 weeks after injury to test the hypothesis that neuropathological damage is proportional to early microglial activation. Persistent microgliosis is associated with a condition of progressive neurodegeneration after repeated mild TBI, termed chronic traumatic encephalopathy (CTE). CTE is officially diagnosed by cytosolic accumulations of phosphorylated TAR DNA binding protein 43 (pTDP43) and hyperphosphorylated Tau in the post-mortem brain. Currently, no animal model of TBI replicates all of these key pathological hallmarks, hindering progress in understanding the causative cellular and molecular factors underlying CTE. GRN KO mice have an age- dependent increase in microgliosis (~7mo) in the absence of injury that precedes the accumulation of pTDP43 (~12-18mo). In Aim 2, chronic histopathological and behavioral effects of repeated concussions will be compared in GRN KO and WT mice over time. We anticipate that persistent activation of microglia in brain- injured GRN KO mice will accelerate pTDP43 accumulation and worsen behavioral deficits, providing a more rapid and efficient model for assessing the links between repeated concussions and the development of CTE pathology. An animal model of CTE will also provide a platform for testing therapeutic interventions.